Food allergy (FA) is a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food. FA affects approximately 5-8% of children and 1-4% of adults and is a growing clinical and public health problem in the U.S. and worldwide. The major obstacle in preventing and treating FA has been our incomplete understanding of its etiology and biological mechanisms. Available evidence suggests that FA is a complex trait determined by multiple environmental and genetic factors. This proposal is built on our ongoing investigation of environmental and genetic factors of FA, and is designed to explore a novel area: epigenomic associations with FA. Epigenetics is defined as the study of heritable changes in gene expression that occur without changing DNA sequences. Epigenomics is the study of epigenetics on a genome-wide scale. While there is no epigenetic or epigenomic data available for FA, epigenetics appears to play an important role in Th cell differentiation and cytokine gene expression. We hypothesize that an integration of clinical, environmental, genetic and epigenetic data represents a promising approach to understand the etiology and biological mechanisms of FA, in particular, this may provide mechanistic insight into how genetic variants and environmental exposures can modify the risk, severity and long-term outcome of FA. The central focus of this proposal is to perform genome-wide mapping to identify epigenetic alterations in FA, and to integrate such data with phenotypic, environmental and genetic data. We will utilize the extensive resources of the Chicago Cohort to address the following specific aims: Aim 1A: We will conduct epigenomic mapping of 600 white children: 300 cow milk allergy (CMA) cases and 300 non-allergic controls from the Chicago Cohort, using the Illumina HumanMethylation27 DNA Analysis BeadChip (Infinium). We will test the hypothesis that epigenetic alterations in venous blood samples are associated with the risk of CMA, after controlling for potentially important covariates and confounders. Aim 1B (Exploratory): We will compare epigenomic patterns between two groups of CMA cases: without vs. with history of anaphylaxis. We will test the hypothesis that epigenomic patterns differ by severity of CMA, after controlling for potentially important covariates and confounders. Aim 2 (Exploratory): We will integrate epigenomic data with our extensive phenotypic, environmental and SNPs data available in the Chicago Cohort, which allow us to simultaneously evaluate the roles of environment, genetics, and epigenomics as well as their interactions in CMA. The findings from this proposed study may transform our understanding of the etiology and biological mechanisms of FA. Unlike genetic variants, epigenetic alternations are potentially reversible. A better understanding of epigenetic mechanisms may lead to the development of new paradigms for prediction, prevention and treatment of FA. Food allergy (FA) is a growing clinical and public health problem in the U.S. and worldwide. The major obstacle in preventing and treating FA has been our incomplete understanding of its etiology and biological mechanisms. This proposal aims to perform genome-wide mapping to identify epigenomic alterations in FA, and to integrate such data with clinical, environmental and genetic data. The study findings should have important implications for developing strategies in prediction, prevention and treatment of FA.